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Micro RNA ‐34/449 controls mitotic spindle orientation during mammalian cortex development
Author(s) -
Fededa Juan Pablo,
Esk Christopher,
Mierzwa Beata,
Stanyte Rugile,
Yuan Shuiqiao,
Zheng Huili,
Ebnet Klaus,
Yan Wei,
Knoblich Juergen A,
Gerlich Daniel W
Publication year - 2016
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201694056
Subject(s) - biology , microbiology and biotechnology , mitosis , rna , cortex (anatomy) , genetics , neuroscience , gene
Correct orientation of the mitotic spindle determines the plane of cellular cleavage and is crucial for organ development. In the developing cerebral cortex, spindle orientation defects result in severe neurodevelopmental disorders, but the precise mechanisms that control this important event are not fully understood. Here, we use a combination of high‐content screening and mouse genetics to identify the miR‐34/449 family as key regulators of mitotic spindle orientation in the developing cerebral cortex. By screening through all cortically expressed mi RNA s in HeLa cells, we show that several members of the miR‐34/449 family control mitotic duration and spindle rotation. Analysis of miR‐34/449 knockout ( KO ) mouse embryos demonstrates significant spindle misorientation phenotypes in cortical progenitors, resulting in an excess of radial glia cells at the expense of intermediate progenitors and a significant delay in neurogenesis. We identify the junction adhesion molecule‐A ( JAM ‐A) as a key target for miR‐34/449 in the developing cortex that might be responsible for those defects. Our data indicate that mi RNA ‐dependent regulation of mitotic spindle orientation is crucial for cell fate specification during mammalian neurogenesis.